tbuckley/cabot-search huggingface dataset:
Two schedules of vincristine, irinotecan and temozolomide (VIT) for patients with relapsed or refractory Ewing sarcoma: A randomized controlled phase 2 trial.
Authors: Jie Xu
Journal: Journal of Clinical Oncology (2023)

11525 Background: Vincristine, irinotecan and temozolomide (VIT) has provided an effective regimen in relapsed or refractory Ewing sarcoma patients. Optimal dose schedule of VIT is still undefined. Methods: We did this phase 2 randomized controlled trial and included patients with relapsed or refractory Ewing sarcoma. They were randomly assigned (1:1) by random number table method to either shorter dx5 schedule (Irinotecan 50mg/m 2 /d D 1-5 , Vincristine 1.4mg/m 2 D 1 ) or protracted dx5x2 schedule (Irinotecan 20mg/m 2 /d D 1-5,8-12 , Vincristine 1.4mg/m 2 D 1,8 ) together with a fixed dose of temozolomide (100mg/m 2 /d D 1-5 ) in both groups. Patients were treated every 3 weeks till progression or unacceptable toxic effects for up to eight cycles. The primary endpoint was objective response rate at 12 weeks (ORR 12w ). The secondary endpoint was progression-free survival (PFS), overall survival (OS) and safety. The study was powered to detect a 30% improvement in the response rate from 20% of dx5 schedule to 50% of dx5x2 schedule (α = 0.1, 1-β = 0.9, one-sided test favoring dx5x2 schedule since the only difference of clinical importance was an improved response with the inconvenient schedule of dx5x2). A sample size of 30 patients per group (60 randomly assigned patients) was required to detect a significant improvement in ORR 12w . Results: Between May 21, 2020, and August 8, 2022, 24 patients were randomly assigned to dx5 schedule while 22 to dx5x2 schedule, respectively. Median follow-up was 10.7 months (IQR 9.7-13.9) in the dx5 group and 8.3 months (IQR 4.4-15.3) in the dx5x2 group. ORR 12w was lower in dx5 group than in dx5x2 group (5 [20.8%] of 24 patients vs 12 [54.5%] of 22; p = 0.019). There was no significant difference in PFS between the two groups (median PFS 2.3 months [95% CI 0.0-4.7] in dx5 group vs 4.3 months [2.7-6.0] in dx5x2 group; hazard ratio [HR] 0.956 [95% CI 0.84-1.09]; p = 0.434). Also, there was no significant difference in OS (median OS 14.8 months [95% CI 12.0-17.6] vs 12.8 months [95% CI 6.9-18.7]; HR 0.957 [95% CI 0.81-1.12]; p = 0.594). Patients in dx5 schedule reported more grade 3 and 4 adverse events (AEs) than dx5x2 schedule, including diarrhea/abdominal pain (23[23.7%] of 97 courses vs 8[8.4%] of 95 courses, p = 0.005), vomiting/nausea (6[6.2%] vs 1[1.15%], p = 0.035). Other common grade 3 and 4 AE ( &gt; 5%) were similar between two schedules (p &gt; 0.05), including fatigue (24[24.7%] vs 14[14.7%]), leukopenia (6[6.2%] vs 8[8.4%]), neutropenia (5[5.2%] vs8 [8.4%]), and anemia (5[5.2%] vs 7[7.4%]). Unfortunately, the isolation policy of COVID-19 significantly restricted the speed of recruiting and the sponsor stopped following support to our study. Conclusions: Protracted dx5x2 VIT schedule showed superior efficacy and favorable tolerability compared with the shorter dx5 VIT schedule in patients with relapsed or refractory Ewing sarcoma. Clinical trial information: NCT03359005 .
Cancer therapy-associated thrombosis: A patient- reported outcomes (PROs) analysis.
Authors: Paris A. Kosmidis, Elena Deligianni, Thanos Kosmidis
Journal: Journal of Clinical Oncology (2023)

e18819 Background: Cancer patients have a higher rate of thrombotic events (TEs) compared to the general population. Site, stage and treatment related factors, among others, contribute to this increased risk. Regarding treatment, various anticancer agents have been linked with increased risk of TEs. However, despite the incidence and impact of TEs, available data is inadequate, and most PRO-based analyses focus on individual agents. This analysis aims to utilise PROs to identify correlations between several anticancer agents and the incidence of TEs. Methods: CareAcross is an online interactive platform which collects Patient Reported Outcomes and provides support to cancer patients based on their condition and needs. Specific cancer treatments are among the collected data. Additionally, breast and lung cancer patients engaging with the platform were asked to report, among others, whether they have had a TE during their cancer journey. Data was aggregated and anonymised in order to evaluate the likelihood of TEs for each cancer treatment. Results: Based on data captured as of February 2023, 2011 breast (13% metastatic) and 573 lung (51% metastatic) cancer patients from 8 (mostly European) countries had provided real world data on cancer treatments and TEs. Among them, 144 (7.2%) breast cancer and 97 (16.9%) lung cancer patients reported TEs. Breast cancer treatments with higher than average association with TEs included aromatase inhibitors (8.1% of 569), tamoxifen (8.0% of 462), trastuzumab (9.0% of 221), CDK4/6 inhibitors (8.7% of 126). Among lung cancer treatments, cisplatin was associated with higher incidence than carboplatin (20.0% of 110 vs 13.4% of 112); others included pembrolizumab (21.8% of 78), pemetrexed (13.2% of 68), alectinib (29.4% of 34), osimertinib (12.1% of 33), afatinib (29% of 31). The Table provides a summary for this subset of anticancer agents. Conclusions: Based on the analysis of PROs from the CareAcross platform, it is confirmed that lung cancer patients have a higher risk of TEs compared to breast cancer patients. Moreover, certain anticancer agents appear to be linked with increased risk of TEs. In breast cancer, aromatase inhibitors and tamoxifen show similar association; in lung cancer, cisplatin appears to be a stronger factor compared to carboplatin. Finally, it is worth mentioning that some immunotherapies and targeted agents in lung cancer were found to have strong association with TEs. More PROs would improve the accuracy of these findings. [Table: see text]
Clinical analysis of the presence of comutations in patients with EGFR-mutated NSCLC.
Authors: Jaime Rubio, Carlota Santolaya, Marina Fernandez, Paula Lucia Villalba, Mercedes Avedillo, Jesus Garcia-Foncillas, Manuel Domine
Journal: Journal of Clinical Oncology (2023)

e21001 Background: EGFR mutation is the most common treatable molecular alteration in non-small cell lung cancer (NSCLC), in particular in adenocarcinoma it can be found in 10-15% of our patients (spanish population). But the presence of other commutations in EGFR mutated tumors and its implications has not been well characterized. Methods: We selected patients diagnosed with EGFR mutation non-small cell lung carcinoma (NSCLC) from February 2021 to March 2022 from 4 hospitals in Madrid (most of them from Fundación Jimenez Diaz University Hospital). EGFR status and the presence of commutations was determined by using the AVENIO Tumor Tissue Targeted Kit (a Next Generation Sequencing test). PD-L1 status was determined by immunohistochemistry assay (22C3 pharmDx). Molecular and clinicopathological characteristics were collected and we performed a descriptive analysis of our population. Results: Of the 48 patients evaluated, 68.8% were women and 31.3% were men. 73% were ECOG 0 and 23% ECOG 1 and only 44% were non-smokers, being 18.8% smokers and 37% ex-smokers, most of them with low consumption. The 91.7% were adenocarcinomas and 8.3% were squamous carcinomas. 43.7% were PD-L1 negative and 10.4% were high expressors (PD-L1 &gt; 50%). Of the stage at diagnosis, 60.4% were stage IV and 16.7% were stage III, with 22.9% being stage I and II. Of the Stage IV patients, 87.7% debuted as patients with high disease burden, with only 13.3% being oligometastatic (oligometastatic being understood as those with less than 5 metastases in 3 different organs, including the primary tumor). 40% of them had brain metastasis at the diagnosis. Of the mutational profile, 50% had an exon 19 deletion, 25% had an L858R mutation and the rest had infrequent mutations (12.5% amplification, 10.4% exon 20 insertion and 6.3% exon 18 mutations). In our cases, we evidence that 56.25% of the patients, analyzed by NGS, had another mutation. Of all of them the most frequent was p53 (seen in 55% of the commutated cases), being less frequent others, such as MET and APC amplification (4.2%) and others with a 2.1% (PI3K, BAP1, KRAS, ALKt or HER2 amplification). Finally, we analyzed the progression-free survival (PFS) and overall survival (OS) of commutated patients vs. non-commutated treated with Osimertinib as a first line treatment and, although it was statistically non-significant due to the small sample size (11 vs 9) and the short follow-up, a very positive trend was seen (log-rank test p = 0.055 and p = 0.136 respectively). Conclusions: With the development of NGS, the presence of other commutations besides EGFR have implications that are still unknown, but it appears that it may cause worse OS and PFS. This should be studied in larger cohorts with longer follow-up.
Final analysis of the phase IB part of the LOC-R01 trial, a non-comparative randomized phase IB/II study of escalating doses of lenalidomide and ibrutinib in association with R-MPV for patients with a newly diagnosed primary central nervous system lymphoma (PCNSL).
Authors: Marion Alcantara, Marion Chevrier, Fabrice Jardin, Anna Schmitt, Caroline Houillier, Lucie Oberic, Olivier L. Chinot, Franck Morschhauser, Frederic Peyrade, Roch Houot, Christine Foulon, Estelle Chauvin, Herve Ghesquieres, Carole Soussain
Journal: Journal of Clinical Oncology (2023)

7566 Background: Results of conventional induction chemotherapies in PCNSL need to be improved. Ibrutinib, a BTK inhibitor, and lenalidomide, an immunomodulatory drug, have shown promising results in the relapse setting, supporting to further assess their combination with standard high-dose methotrexate-based chemotherapy. Methods: Patients (pts) with newly diagnosed PCNSL, aged 18 to 60, were randomized to receive four 28-day cycles of either ibrutinib or lenalidomide in combination with R-MPV (rituximab, methotrexate, procarbazine, vincristine and prednisone) in a 3+3 design for ibrutinib 420/560/280 mg (D3 to D14 and D17 to D28) and lenalidomide 20 mg D1 to 14/20 mg D1 to 21/15 mg D1 to 21. Responder pts then received a consolidation with R-Cytarabine and an intensive chemotherapy with autologous stem cell transplantation. The objective of the phase IB study was to define the recommended phase II dose (RP2D) based on the dose-limiting toxicity (DLT) occurring during the first induction cycle. We present the results of the phase IB, including the toxicities that occurred throughout induction therapy. Results: 26 pts (median age 52) were randomized, 13 in each treatment group. Four DLTs (/21 evaluable pts) have been observed: grade 5 aspergillosis and pneumocystosis (N=1, ibrutinib 560 mg and concurrent high-dose corticosteroids without prophylaxis), grade 4 catheter-related infection &gt; 7 days (N=1, lenalidomide 20 mg D1-14) and grade 3 increased alanine aminotransferase &gt; 7 days (N=1, lenalidomide 20 mg D1-14 and N=1, lenalidomide 15 mg D1-21). RP2D of ibrutinib and lenalidomide were 560 mg (D3-14 and D17-28) and 15 mg (D1-21) respectively, in combination with R-MPV. One Lyell’s syndrome was reported as a serious adverse event (AE) at cycle 2 in the lenalidomide arm. Grade ≥3 treatment-related AEs occurring in ≥2 pts at any time during induction treatment are detailed in the table. After 4 induction cycles, 3/11 evaluable pts had CR/CRu and 7/11 had partial response (PR) in the ibrutinib group. In the lenalidomide arm, 6/10 evaluable pts had CR/CRu and 4/10 had PR. Survivals will be presented. Conclusions: Targeted induction immunochemotherapy with ibrutinib or lenalidomide and R-MPV is feasible for newly diagnosed PCNSL and shows promising response rates. Adverse events should be monitored carefully. The phase II part of the study is ongoing and opened to patients up to 65 years old. Clinical trial information: NCT04446962 . [Table: see text]
Analysis of racial disparities accounting for treatment received in chronic lymphocytic leukemia: A real-world cohort analysis.
Authors: Adam Kittai, Ying Huang, Seema Ali Bhat, Abi Clark, Michael R. Grever, Melyssa Roberts, Kerry Anne Rogers, Anna Teschemaker, Maria Munoz-Sagastibelza, Jennifer Ann Woyach, Jacqueline Claudia Barrientos
Journal: Journal of Clinical Oncology (2023)

7533 Background: Recent population-based studies have shown that Black patients (pts) with CLL have worse overall survival (OS) than White pts with CLL. These studies could not account for the use of modern therapies, CLL prognostic variables, or comorbidity and thus the root cause of this disparity remains unclear. Here, we use the Flatiron Health Database (FHD) to study this disparity, while accounting for disease-specific variables and treatment (tx) received. Methods: Retrospective analysis of pts with CLL in the FHD treated between 2002 to 2022 was performed. Pt characteristics such as age at diagnosis (dx), year (yr) of dx, months (mos) from dx to first tx, race, sex, IGHV status, ECOG performance status (PS), and use of small molecule inhibitors at any time (including BTK inhibitors, venetoclax, PI3K inhibitors, and lenalidomide) were collected and analyzed. OS was measured from tx start. Multivariable cox regression (MVA) was used to determine adjusted odds of survival. Results: 13646 pts with CLL were identified. Mean age at dx was 65.3 yrs, and mean time from dx to tx was 32.3 mos. 81.2%, 8.4%, and 10.4% of pts were White, Black, or other race, respectively, and 63.2% of pts were male. 61.4% of pts were IGHV unmutated, and 89.1% of pts had a ECOG PS 0/1. 58.7% of pts were treated with a small molecule inhibitor at any point during their tx. After a median follow-up of 5.3 yrs, the median OS was 10.5 yrs (95% CI: 10.2-10.8). Black pts were younger at dx (63.1 vs 65.4), had shorter time to first tx (23.6 mo vs 34 mo), were more likely to be IGHV unmutated than White pts (83% vs 60.1%), and had more small molecule inhibitor use (69% vs 58.5%). These differences were all statistically significant (p &lt;0.01). 90.8% and 89.1% of Black and White pts had an ECOG PS of 0/1, respectively. Median OS for Black pts was 10 yrs (95% CI: 9.1-11.1) vs 10.5 yrs (95% CI: 10.2-10.8) for White pts. On MVA, Black pts had higher risk of death than White pts of the same age despite increased use of small molecule inhibitor (Table). However, the interaction between age and race was also significant, indicating a decreasing disparity between Black and White race as pts aged. Time to first tx, IGHV unmutated status, and ECOG PS were also independently associated with worse OS. Conclusions: Black race especially at younger age was independently associated with worse OS despite the use of small molecule inhibitors, IGHV status, and ECOG PS. [Table: see text]
Methylation classifier array and classification of solitary fibrous tumors.
Authors: Zachary L Chelsky, Farres Obeidin, Borislav A. Alexiev, Lucas Santana-Santos, Drew Duckett, Stephanie Parker, Joseph Baczkowski, Seth Pollack, Erica Vormittag-Nocito, Lawrence J Jennings
Journal: Journal of Clinical Oncology (2023)

e23522 Background: Solitary fibrous tumors (SFTs) are fibroblastic tumors which carry a characteristic NAB2::STAT6 gene rearrangement. SFTs represent a heterogenous group that may arise in multiple locations and have variable risk of progression. Despite a consistent oncogenic driver, there is little biological data explaining this variability. Recently, the German Cancer Research Network (DKFZ) have modified their brain tumor methylation classifier for use in sarcomas. We subjected solitary fibrous tumors diagnosed at our institution to a validated, in-house sarcoma methylation array classifier modeled after that of the DKFZ in order to assess for differences in methylation patterns that may account for biological or clinical variances. Methods: Twenty-eight primary site SFTs from 2011-2021 were subjected to the sarcoma methylation classifier. Histologic diagnosis was confirmed by STAT6 immunohistochemistry or by the presence of the NAB2::STAT6 fusion. The methylation classifier was run on the Illumina iScan platform and the resulting IDAT files were analyzed via a custom bioinformatics pipeline. The sarcoma classifier was trained using the same samples and normalization strategies used by the DKFZ group and validated using the same publicly available samples. Results: Methylation data for each tumor was collected, given a classification score, and visualized by t-distributed stochastic neighbor embedding (t-SNE). We noted three distinct groups of SFTs on the t-SNE plot. Group 1 was comprised of all eight intracranial SFTs and were correctly classified as SFT (classifier score ≥0.9). Group 2 contained nine pleural-based tumors and one SFT each from the mediastinum and bladder wall. Classification was successful in only seven of eleven tumors. Group 3 SFTs predominantly arose in the soft tissues or bone (two pelvis, four extremity, and one mediastinum) and all failed accurate classification. Finally, two orbital SFTs stratified separately from all groups on t-SNE plot but did achieve an appropriate classification. There were no significant differences in grade or risk stratification among the three groups. Conclusions: Our preliminary data show differential clustering based on tumor location, suggesting biological differences between intracranial, pleural/visceral, and connective tissue locations. These results highlight the heterogeneity of these tumors and the inadequacy of the current methylation classification scheme for SFT. Future directions will include analysis of additional cases, gene expression patterns, and outcome data.
Analysis of significant weight gain in patients using alectinib for ALK-positive lung cancer.
Authors: Barend Joël Sikkema, Simon de Leeuw, Melinda Pruis, Mostafa Mohseni, Geerten Dieuwert Marijn Veerman, Marthe Paats, Daphne W Dumoulin, Egbert F. Smit, Annemie M.W.J. Schols, Ron H.J. Mathijssen, Elisabeth Van Rossum, Anne-Marie C. Dingemans
Journal: Journal of Clinical Oncology (2023)

e21138 Background: Alectinib is standard of care for metastatic anaplastic lymphoma kinase positive (ALK+) nonsmall cell lung cancer (NSCLC). Weight gain is an unexplored side effect reported in ~10%. To prevent or intervene alectinib-induced weight gain, more insight in its extent and etiology is needed. Methods: Change in body composition was analyzed in a prospective series of 46 patients with ALK+ NSCLC, treated with alectinib. Waist circumference, skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were quantified using sliceOmatic software on computed tomography (CT) images at baseline, three months (3M) and one year (1Y). To investigate an exposure-toxicity relationship, alectinib plasma concentrations were quantified. Four patients with &gt; 10 kg weight gain were referred to Erasmus MC Obesity Center for in-depth analysis (dietary habits, metabolic/endocrine assessment). Results: Mean increase in waist circumference was 9 cm (9.7%, p &lt; 0.001) in 1Y with a 40% increase in abdominal obesity (p = 0.014). VAT increased 10.8 cm2 (15.0%, p = 0.003) in 3M and 35.7 cm2 (39.0%, p &lt; 0.001) in 1Y. SAT increased 18.8 cm2 (12.4%, p &lt; 0.001) in 3M and 45.4 cm2 (33.3%, p &lt; 0.001) in 1Y. The incidence of sarcopenic obesity increased from 23.7% to 47.4% during 1Y of treatment. Baseline waist circumference was a positive predictor of increase in VAT (p = 0.037). No exposure-toxicity relationship was found. In-depth analysis showed increased appetite in two patients and metabolic syndrome in all four patients. Conclusions: Alectinib caused significant increased abdominal obesity, sarcopenic obesity, SAT and VAT quickly after initiation. This may lead to serious metabolic disturbances in long-surviving patients.[Table: see text]
Sex differences in localized gastrointestinal stromal tumor.
Authors: Kjetil Boye, Ivar Hompland, Jeanne-Marie Berner, Leonardo A. Meza-Zepeda, Toto Hølmebakk
Journal: Journal of Clinical Oncology (2023)

e23511 Background: Sex plays an important role in the incidence and prognosis of several cancer types. Male patients with gastrointestinal stromal tumors (GISTs) have inferior outcomes compared to women, but the reasons behind the sex differences are not well understood. This study aimed to investigate whether sex was a prognostic factor in localized GIST and to explore the relationship between sex and established clinical, molecular and histopathological characteristics. Methods: The study cohort is population-based and consisted of patients who underwent surgical resection of primary, non-metastatic GIST at Oslo University Hospital, Norway between January 2000 and September 2017. Recurrence-free survival (RFS) was the primary endpoint. Mutation analysis was performed by Sanger sequencing or by the AmpliSeq for Illumina Cancer Hotspot Panel version 2. Results: The study cohort comprised 409 patients, 202 women and 207 men. There were 275 gastric tumors (67.2%) and 134 non-gastric tumors (32.8%). Disease recurrence was recorded in 87 patients (21%) after a median follow-up of 64 months. Men with gastric tumors had inferior RFS compared to women (HR 2.18; 95% CI 1.07-4.45; P= 0.029), while there was no difference for non-gastric tumors (HR 0.77; 95% CI 0.44-1.33; P= 0.341). There was a substantial sex variation in the type of primary KIT mutation related to tumor location. Men with gastric tumors had a deletion or insertion-deletion that involved codons 557 and 558 (del557/558) more than twice as frequently as women (34% versus 16%; P= 0.008). Men also had slightly larger tumors (mean 6.6 cm versus 5.5 cm; P= 0.035) and more often tumors located in the upper third of the stomach, but there was no difference in mitotic count (23% versus 22% with &gt; 5 mitoses per 5 mm 2 ). There was no difference in adjuvant imatinib treatment between men and women. No sex differences in primary mutation, tumor size or mitotic count were observed for non-gastric tumors. When KIT del557/558 mutation was included in the Cox regression analysis for gastric tumors, sex was not significantly associated with RFS (HR 1.49; 95% CI 0.70-3.18; P= 0.303), while del557/558 mutation was a strong prognostic factor (HR 6.40; 95% CI 3.17-12.94; P&lt; 0.001). Del557/558 mutation was not associated with RFS in non-gastric tumors (HR 0.67; 95% CI 0.33-1.35; P= 0.262). Conclusions: Women with localized, gastric GISTs had a lower risk of recurrence compared to men. There was no sex difference in outcome or baseline characteristics for non-gastric tumors. Men with gastric tumors more often had KIT del557/558 primary mutations, which may explain their inferior outcome. The observed sex difference in primary mutations in GISTs is unexplained and should be further explored.